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Tissue-resident memory T cells (T RM ) are newly defined memory T cells (T M ) distinct from circulating T M  subsets which have the potential to mount rapid protective immune responses at the site of infection. However, very limited information is available regarding the role and contribution of T RM  in vaccine-mediated immune responses in humans at the site of infection. Here, we studied the role and contribution of tissue resident memory T cells (T RM ) located in the terminal ileum (TI) (favored site of infection for  S . Typhi) following oral Ty21a immunization in humans. We examined TI-lamina propria mononuclear cells (LPMC) and intra-epithelial lymphocytes (IEL) CD8+ T RM  subsets obtained from healthy volunteers undergoing medically-indicated colonoscopies who were either immunized with Ty21a or unvaccinated. No significant differences in the frequencies of LPMC CD8+ T RM  and CD8+CD69+CD103– T cells subsets were observed following Ty21a-immunization. However, LPMC CD8+ T RM  exhibited significantly higher levels of cytokines (IFN-γ, IL-17A, and TNF-α)  ex-vivo  in Ty21a-vaccinated than in unvaccinated volunteers. LPMC CD8+ T RM   S . Typhi-specific responses were evaluated using  S . Typhi-infected targets and found to produce significantly higher levels of  S . Typhi-specific IL-17A. In contrast, LPMC CD8+CD69+CD103- T cells produced significantly increased  S . Typhi-specific levels of IFN-γ, IL-2, and IL-17A. Finally, we assessed CD8+ T RM  in IEL and observed that the frequency of IEL CD8+ T RM  is significantly lower following Ty21a immunization. However,  ex-vivo  IEL CD8+ T RM  elicited by Ty21a immunization spontaneously produced significantly higher levels of cytokines (IFN-γ, IL-17A, IL-2, and TNF-α). This study provides the first demonstration of the effect of oral Ty21a vaccination on CD8+ T RM  subsets (spontaneous and  S . Typhi-specific) responses in the LPMC and IEL compartment of the human terminal ileum mucosa, contributing novel information to our understanding of the generation of mucosal immune responses following oral Ty21a-immunization.

frontiers in immunology

Attenuated Oral Typhoid Vaccine Ty21a Elicits Lamina Propria and Intra-Epithelial Lymphocyte Tissue-Resident Effector Memory CD8 T Responses in the Human Terminal Ileum